Continuous open-cell polymeric foams containing living cells

ABSTRACT

A polymeric foam with continuous, open-cell pores containing living cells suitable for medical applications and methods for preparing these foams. The microporous foams are of controlled pore size that may be utilized in a variety of applications. In general, the foams are characterized in that the pores are continuous and open-celled. In preparing the foams, an organic polymer is melted and combined with a selected solid crystalline fugitive compound, that melts above about 25° C. and/or that sublimates at above about 25° C. or can be extracted, to produce a substantially isotropic solution. The solution is cooled under controlled conditions to produce a foam precursor containing the solidified fugitive composition dispersed through a matrix of the organic polymer. Crystals of fugitive composition are then removed by solvent extraction and/or sublimation, or a like process to produce microcellular foams having a continuous, open-cell structure. After removing the fugitive composition, living cells capable of producing biologically active products are added to the pores to produce a foam containing living cells.

This is a division of application Ser. No. 08/106,064 filed Aug. 13,1993 which is now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to microporous thermoplastic foams andmicrotextured films and methods for preparing these foams and films.More specifically, the invention provides a method for producing foamswith controlled pore size, chemical reactivity and mechanicalproperties, as well as microtextured surfaces with modulatedmicroroughness, lyophilicity, and chemical reactivity that may beutilized in a variety of applications, including drug delivery systems,constructs for bone and cartilage regeneration, constructs for organgeneration, filters for protein fractionation, matrices for gas andfluid filtration, templates for three-dimensional cell cultures,bioreactor substrate material, constructs containing immobilizedchemical and biological reagents for use in continuous chemical andbiochemical processing, and the like.

2. Description of the Related Art

It is expected that there are many potential biomedical applications formicrocellular foams although not necessarily disclosed in the prior art.Among the potential uses are, use as timed-release drug deliverysystems, neural regeneration pathways, templates for skingeneration/regeneration, vascular replacements, and artificial bonetemplates. Specific areas of immediate biomedical significance includeuse of absorbable microcellular foams for bone and cartilageregeneration applications as well as the use of microcellular foams fororgan generation, components of bioreactor cartridges, such as thoseuseful for the production of growth factors, microcellular filters forprotein fractionation, microcellular matrices for gas and fluidfiltration, and microcellular constructs containing immobilized chemicaland biological reagents for use in continuous chemical and biochemicalprocessing, some of these applications are discussed in the patentliterature.

For instance, U.S. Pat. Nos. 4,902,456 and 4,906,377 discuss themanufacture of fluorocarbon porous films frompoly(tetrafluoroethylene-co-perfluoroalkyl vinyl ether) (PFA) orpoly(tetrafluoroethylene-co-hexafluoropropylene) (FEP). The porous filmsare permeable to both liquids and gases and can be used as filtrationmedia. In producing the films, a mixture is formed that comprisesbetween about 10 to about 35 wt. % FEP or PFA polymer with the remainderbeing a solvent (porogen) chlorotrifluorethylene oligomer which permitsliquid--liquid phase separation upon cooling from elevated temperatureand subsequently solidification of the polymer. The mixture is heatedand extruded to form a film or hollow fibers which are then quenched toeffect phase separation of the fluorocarbon polymer from the solvent.The extrudate is quenched by passing it over a chill roller which coolsthe extrudate to a temperature that causes microphase separation ofpolymer and solvent. The solvent is separated from the polymer byextraction and the resultant microporous polymeric membrane is driedunder restraint in order to minimize or prevent membrane shrinkage andcollapse.

U.S. Pat. No. 4,603,076 relates to hydrophilic flexible foams that aresaid to be particularly suited for use in external biomedicalapplications. The polyurethane films are produced by blowing a methylenediphenyl diisocyanate (MDI) prepolymer with a substantially non-aqueousblowing agent, such as pressurized air. The prepolymer is thenpolymerized with polyoxyethylene polyol having at least two hydroxylequivalents per mole. The hydrophilic foam may be extruded, knifecoated, or cast into sheets.

Likewise, U.S. Pat. No. 5,071,704 relates to specific foams into which areservoir layer maybe incorporated for allowing controlled release ofvapors or liquids of an active compound into the surroundingenvironment. This is accomplished by incorporating a diffusionrate-limiting membrane layer, into a laminate of the foam, whichcontrols the rate at which the active compound diffuses to the surfaceof the laminate and vaporizes or dissolves into the environment.

U.S. Pat. No. 5,098,621 relates to flexible foam substrates forselectively releasing and dispensing active ingredients. The compositematerial includes an open foam substrate containing particles ofmicropackaged active ingredient liquids or solids, formed with frangiblecontainment walls, for breaking and releasing active ingredients inresponse to a defined level of stress.

Whereas the above patents indicate methods for making foams,microcellular foams made from biomedically significant polymers are ofparticular interest. Further, production of polymeric microporous foamshaving continuous cellular structures has not been exploited to anygreat extent. Microcellular foams have been produced using variousmaterials and processes, but these foams cannot be produced frombiomedically useful polymers using the two traditional methods: lowtemperature freeze drying and salt leaching, or the more recenttechnique, thermally induced phase separation (TIPS). Salt leaching hasseveral limitations including the factor that it is often difficult toform small micropores with salt and it requires a high salt loading toachieve interpore channeling to produce continuous microporous foams.Further, there is a limited availability of solvents for polymersintended for biomedical use. Freeze drying also has its limitations.Specifically, there is a limited availability of crystallizable solventsthat can be sublimed at the low temperatures characteristic of thefreeze drying process. Further, the freeze drying process is a batchprocess which imposes limitations in terms of the size and shape of thefoam produced.

TIPS, in concert with low-temperature freeze-drying technology, has beenused to produce microcellular foams made of dextran, cellulose, andpolystyrene. Limitations associated with available materials andsolvents have generally restricted the growth of TIPS foam formationtechnology. In the TIPS process, the pore formation is preceded by aliquid--liquid, liquid-solid, or solid-liquid phase phase separationthat is difficult to control. Further, the TIPS process requiressolidifying the solvent-polymer mixture with rapid cryogenic quenching.This type of quenching presents an obstacle to large scale manufacturingprocesses.

Production of microcellular foams with controlled chemical andmechanical properties and morphology would facilitate the use ofbiologically safe polymers for the production of microcellular foams forbiomedical applications. The growing demand for polymeric microcellularforms in several areas of advanced technology represent an urgent needfor developing a method for converting non-bioabsorbable andbioabsorbable polymers, which cannot be processed in a traditionalmanner, to microcellular foams.

There exists a need for a continuous, open-cell microcellular foam, anda process for producing such a foam, on a typical manufacturing scale,from organic polymers suitable for biomedical applications, without needfor complex new equipment to make the foams. Further, the process shouldbe readily applicable to a broad range of thermoplastic polymers whichcan be absorbable or non-absorbable. Representative non-absorbablepolymers include, but are not limited to, polyamides, aromaticpolyesters, and polyolefins, while the absorbable type of polymers canbe based totally or partially on polymers such as polylactic acid,polyglycolic acid, polyalkylene oxalate, polydioxanone, andpolyanhydride. Further, the process should allow some measure of controlof the size of the open-cell pores or voids so that foams may be customtailored for particular applications, such as timed-release drugdelivery systems, constructs for regeneration of bone, cartilage, and amultiplicity of soft tissues (including skin and liver) constructs fororgan generation, filters for protein fractionation, matrices for gasand fluid filtration, constructs for use in bioreactor cartridges usedfor continuous chemical and biochemical processing, and the like. Theinner and outer microporous cell surfaces can be chemically activated toallow the creation of chemically active functionalities which can beused to bind biologically active agents ionically or covalently.

SUMMARY OF THE INVENTION

The invention provides microcellular foams produced by a process thatallows controlled formation of continuous open-cell pores or voids usinga broad range of polymeric thermoplastic precursors and followingprocessing schemes that are adaptable to a number of large manufacturingschemes. The foams have a matrix of an organic polymer with continuous,open-cell pores dispersed throughout the matrix, and are produced by aprocess that requires the blending of molten polymer with a relativelylow molecular weight fugitive compound that is a crystalline solid thatmelts at temperatures above about 25° C. and/or can be sublimed andextracted in a broad range of temperatures above about 25° C.

In producing the microporous foams, an organic polymer is co-melted withthe solid, crystalline, fugitive organic compound to produce asubstantially isotropic solution. The isotropic solution is solidifiedby quenching, either by conventional cryogenic techniques or by ambientcooling, using a water or air as a convection medium, to produce a foamprecursor. In most cases, the foam precursor is a matrix of 25 theorganic polymer with a fugitive compound dispersed as a microcrystallinesolid therein and a few cases as an intermolecular moiety with nodistinct crystalline lattice. The fugitive compound can be removed byseveral techniques, depending upon the specific composition. Typically,the crystals are removed by leaching with a solvent or sublimationthrough heating under vacuum. The resultant continuous, open-cell foamsare microporous and suitable for a variety of applications, among whichare medical applications.

The inventive microporous foams can be made in a variety of shapes,depending upon requirements. For example, microporous foam in the formof hollow fibers, catheters, films or sheets, can be produced byextrusion of the molten, substantially isotropic solution that containsthe organic polymer and the fugitive composition. The extrudate,consisting of a foam precursor, may then be treated to remove thefugitive composition either by leaching with a solvent, and/orsublimation of the composition. Alternatively, the foam precursor may bein the core of a fiber extrudate so that upon removal of the fugitivecompound, an extrudate, with a hollow core and solid sheath is obtained.

Different forms of filamentous foams having a high surface area tovolume ratio, may be used to fabricate bioreactors for producing a rangeof biological products. For example, living cells maybe cultured on theextensive surface area provided by these hollow fibers or tubes and,since the foam is of an open-cell nature, nutrients may readily besupplied to the cells and products readily removed for furtherprocessing and use. The structure of the foam also allows the faciletransport of waste products.

Further, the open-cell foams may be fabricated of a bioabsorbablepolymer, so that these may be implanted into a living body with orwithout the incorporation of certain bioactive agents, such as growthfactors, for tissue regeneration purposes. Thus, the implantedbioabsorbable foam may be shaped and fitted as a prosthetic implant orconstruct to repair skeletal or soft tissues so that as bone or specificsoft tissue grows into the bioabsorbable foam implant, the implantgradually absorbs until the skeletal or soft tissue structure isrepaired and the implant completely absorbed. Specifically for bonegeneration, the pores of the bioabsorbable construct may be doped withbone morphogenic protein, or cells producing such proteins and otherdesirable biologically active substances, to promote healing and bonegrowth. Likewise, constructs may be fabricated for use in repairingligament or soft tissue of living bodies utilizing bioabsorbablepolymeric matrices, with suitable pharmacologically active and/orbiologically active materials or cells producing such active materials,in the pores of the construct.

The foams which can be processed in the precursor stage by extrusion,casting or other methods for production of shaped articles, due to thecustom tailored nature of the pores, are also useful as devices for thetimed delivery of drugs, for instance transdermally. Thus, given thediffusion kinetics of a certain medicament, a foam may be customtailored with a particular pore size which can be doped with themedicament to release the medicament to the patient at a controlled,desired rate.

The foam-precursor technology that is the subject of this invention canbe used on a limited basis to create a thin microporous layer on theouter-most boundaries or surfaces of polymeric articles by dipping sucharticles in the fugitive composition medium to co-dissolve with thepolymer comprising the base of the polymeric articles. Depending uponthe dipping time and temperature, the thickness of the foamy parts canbe modulated. This thin microporous layer can be from one to a few poresin thickness and can provide a means for surface microtexturing.Surfaces with variable foam depths can be achieved on high meltingand/or low solubility polymers, such as polyetheretherketone (PEEK) andultra high molecular weight polyethylene (UHMWPE). Orthopedic implantswith porous outermost components facilitates bone-ingrowth into theimplant and hence enhances development of mechanical stability. Theperformance of implants with microporous or textured surfaces can befurther improved by chemical activation of the inner and outer cellwalls by a process such as phophonylation. An alternate method tocreating the desired surface morphology is obtained using the isotropicsolution as a dipping medium, instead of the fugitive composition.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides microcellular foams having a continuous,open-cell structure and a process for preparing such foams. Theinvention process permits a degree of control over the range of poresizes so that the foams may be custom-tailored for specificapplications. The applications include, but are not limited to,timed-release drug delivery systems, constructs for hone, cartilage andsoft tissue regeneration, organ generation, filters for proteinfractionation, microcellular matrices for gas and fluid filtration,bioreactors containing immobilized chemical and biological reagents foruse in continuous chemical and biochemical processing to produce usefulproducts.

Conventional foams, produced by traditional methods of foam formation,have voids or pores ranging from 50 to 100 microns in diameter. By somedefinitions, microcellular foams are those containing cells less than 50microns in diameter. However, in the specification and claims, materialsreferred to as microcellular foams are those foams containing voids orpores of varying geometries, that are suitable for biomedicalapplications. Such foams preferably contain pores or voids withdimensions of from about 1 to about 400 microns, most preferably fromabout 5 to about 200 microns.

Foams, according to the invention, may be made from suitable organicpolymeric materials, including the bioabsorbable and non-bioabsorbablethermoplastic polymers. The non-bioabsorbable medically significantpolymers include the polyamides, polyesters, and polyolefins. Thebioahsorbable polymers include poly(dioxanone), polyglycolic acid,polylactic acid, polyalkylene oxalates, polyanhydrides and copolymersthereof.

Depending upon the polymer selected and the size and distribution ofvoids or pores within the foam, the foams may range in mechanicalproperties from flexible to semi-flexible to rigid. Thus, foamsaccording to the invention may be tailored for specific uses byjudicious selection of polymer, and void or pore size, depending uponthe intended use of the foam construct.

In order to prepare the foams according to the invention, a "fugitivecomposition" is required. These fugitive compositions are solidcrystalline compositions that have molecular weights of less than about300 daltons and that are able to form a substantially isotropic solutionwhen combined with the molten polymer that will form the substrate ofthe foam. Upon cooling of the substantially isotropic polymer-fugitivecompound solution, the fugitive compound should separate from thepolymer by crystallizing or forming inter-macromolecular entities. Thisis realized through crystallization-induced microphase separation(CIMS). These crystals or entities may then be subsequently removed fromthe solidified polymer to produce voids or pores in the spaces theypreviously occupied. The preferred fugitive compound are those solid,crystalline compositions that melt at temperatures above about 25° C.;and those crystalline solid compositions that sublime at temperaturesabove about 25° C. and that may also be extracted with solvents.Examples of suitable fugitive compounds include salicylic acid,naphthalene, phenanthrene, anthracene, and tetramethylene sulfone.

Since the foams (including thin, foamy upper-most layers or surfaces) ofthe invention are produced using a solid that crystallizes, the size ofthe voids or pores may be controlled by controlling the relative ratesof crystal growth and nucleation. Thus, for example, all other thingsbeing equal, if it is desired to produce smaller pores, then conditionsmust be selected to favor nucleation over crystal growth. This willensure the presence of a relatively larger number of relatively smallcrystals dispersed throughout the solidified polymer matrix (the foamprecursor). The crystals may then be removed from the foam precursor,either by (1) sublimation under suitable heat and/or vacuum, or (2)extraction with a solvent under suitable heat, (3) or both; to produce afoam containing small pores. If, on the other hand, a foam with largerpores or voids is desired, then process conditions should be modified tofavor crystallization over nucleation. Under these circumstances, fewercrystal nuclei will be produced and the fugitive composition willcrystalize into relatively fewer large crystals in a foam precursor.Upon removing these crystals from the foam precursor, relatively largervoids or pores will be produced in the open-cell foam.

In the process for producing the foams of the invention, the selectedpolymer is typically heated to above its melting temperature, to form apolymeric melt. This melt is combined with the selected fugitivecomposition that melts at above 25° C. of that sublimates at above about25° C. The combination of molten polymer and fugitive compound producesa substantially isotropic solution. This solution may be solidified toproduce a foam precursor including a solid polymeric matrix withcrystals of the fugitive material dispersed throughout the matrix. Asexplained above, the relative size of the crystals may be determined byjudicious selection of processing conditions. It is important to notethat the quenching of the substantially isotropic solution to producethe foam precursor is not necessarily conventional cryogenic quenchingwherein the solution is chilled by liquid nitrogen or dry ice (frozencarbon dioxide). Instead, the quenching step may be carried out byconvective cooling with air or cooling in a water bath. This flexibilityof the process of the invention is particularly important in that itallows the extruding of the substantially isotropic solution withoutneed for cryogenic cooling of the extrudate as it exits the extrusiondye. Similarly, the casting of the foam precursors can be simplified.

Once the foam precursor is produced, regardless of whether byconventional cryogenic quenching or by water or air cooling, thefugitive composition, now finely dispersed throughout the foamprecursor, must be removed in order to form the continuous, open-cellpores characteristic of the foams of the invention. These fugitivecomposition crystals may be removed by leaching with a solvent for thecrystals, that is not a solvent for the polymer matrix. Thus, animportant consideration in selecting the solvent is that it should besoluble in a solvent that is not a solvent for the organic polymer fromwhich the foam will be made. Alternatively, if the solid crystallinematerial is one that sublimates at a temperature above 25° C., then itis important to select a polymer that retains its physical integrity byhaving a melting point (Tm) and/or glass transition temperature (Tg)well above the prevailing sublimation temperature and does not degradeat around the sublimation temperature of the solid fugitive compound.

The proportion of organic polymer and fugitive composition that must bemixed to produce a foam will vary depending upon the percentage of voidsand the size range of the voids desired within the foam. Thus, if alarge percentage voids is required, then a relatively larger proportionof the fugitive compound is added to the organic polymer. Minimum poredimensions can be achieved with fugitive compositions proportions thatallow only formation of inter-macromolecular entities. Typically,however, in order to produce a foam for biomedical applications, foamsmust have a percent voids ranging from about 25 to about 90 percent,more typically 50 to 80 percent, by volume. To produce such foams, fromabout 5 to about 90 wt. % fugitive composition should be added to thepolymer; preferably, from about 10 to about 75 wt. % fugitivecomposition, based upon the combined weights of the polymer and fugitivecomposition and on the assumption that the fugitive composition andpolymer have approximately similar densities.

It is known that certain polymeric materials do not readily form asolution with common organic solvents to create a porous or "foam-like"surface on the polymeric substrates. These are referred to as "polymersnot readily soluble in conventional solvents." Among these polymericmaterials are polyether-etherketone (PEEK), certain aromatic liquidcrystalline polymides, polyesters and the like. In order to create amicroporous morphology in the outer-most layers as surface layers, ormicrotexture the surfaces of substrates, especially films, of polymericmaterials, according to the invention the polymeric material issubjected to hot, molten fugitive composition for a period of timesufficient to co-dissolve the surface of the film (or any other shapedarticles) to a desired extent. Thereafter, the substrate is cooled andthe solid crystalline material is removed by sublimation and/orextraction with a solvent, as explained above. As a result, the surfaceof the substrate exhibits continuous microporosity or is microtexturedwith pores or voids.

The invention also provides polymeric substrates with thin, continuouslyporous or microtextured surfaces. The microtexturing process accordingto the invention produces surfaces that have a porous texture with poresizes ranging from less than about 1.0 microns up to about 20 microns indiameter in the surface of organic polymeric films and other substrates.In a broader sense, implants with modified surfaces and immediatesubsurface micromorphology can be prepared by one of two methods. In afirst method, the implant is coated with a thin layer of the isotropicsolution containing both the desired polymer co-dissolved with thefugitive composition. The coating is then quenched, by a suitableprocess, to produce a thin layer of foam precursor that adheres to thesurface of the implant. The fugitive composition is then removed fromthe foam precursor layer by solvent extraction, sublimation, orcombination of these processes. The result is an implant with a thinmicroporous foam coating that allows tissue ingrowth so that the implantis better anchored in the body. The pores of the foam layer may befilled with pharmacologically or biologically active materials tofacilitate healing, reduce risk of infection, and promote tissue growth.

In the event that the implant is fabricated from a polymeric compositionor a polymeric composite, then the implant may be microtextured bycoating with a medium containing a fugitive composition. The coatedimplant is then subjected to conditions that will cause the polymericsurface of the implant to co-dissolve or co-melt with the fugitivecomposition. Thus, the outer surface of the composite or polymer implantis converted into a foam precursor. This foam precursor can then betreated by solvent extraction or sublimation or both to remove thefugitive composition to produce a microtextured or microporous surface.The invention also provides bi-component constructs that include a foamcore with a solid polymeric skin or surface layer surrounding the core.Such bicomponent constructs may be readily produced by several methodsincluding, for instance, subjecting foam filaments produced, asdescribed above, to heat to cause the outer surface to melt and flow andthereby form an outer skin. Alternatively, filaments maybe extruded alower melting point polymeric sheet to facilitate subsequent melting ofthe outer layer to form the polymeric skin.

When the foams of the invention are intended for implantation into aliving patient, then they maybe supplied with suitable medicaments,including growth factors, pharmacologically active compounds, andbiologically active compounds or living cells capable of producing suchbiologically active compounds. The medicaments include anti-bacterialagents, anti-inflammatory agents, and the like. The biologically activeagents include for example, insulin, insulin-like growth factor (IGF),fibroblast growth factor (FGF), epidermal growth factor (EGF),platelet-derived growth factor (PDGF), and the like. As a generalprincipal, the foams may be doped with any agent or living cell capableof producing that agent in order to enhance the effectiveness of thefoam in its intended function in the body. In one embodiment, the foamsmay be doped with a slightly soluble pharmaceutical product that may beadded with the fugitive composition. The resultant foam precursorproduced may be subjected to steps for removing the fugitive compositionthat result in retaining the pharmaceutical product in the voids orpores of the foam. Thus for instance, if the pharmaceutical product hashigher thermal stability than a fugitive composition that is able tosublimate, then removal of the fugitive composition by sublimation willpermit the retention of the medicament in the pores of the foam.

The following examples illustrate certain embodiments of the inventionand do not in any way limit the scope of the invention as describedabove and claimed hereafter.

EXAMPLES Example 1

Nylon 6 Microporous Foam Using Salicylic Acid As the FugitiveComposition

Nylon 6 fibers were heated with solid salicylic acid to form a 10% (byweight) Nylon 6 solution. The solution was heated close to, but notexceeding 230° C., in an inert atmosphere to produce an isotropicsolution. The processing vessel was then quenched in 25° C. water bath.The solid foam precursor obtained was then heated to 78° C. while vacuumwas applied to remove the salicylic acid by sublimation.

Characterization by light microscopy revealed a porous, foam morphology.Continuous porosity was verified by monitoring the fast transport of anaqueous dye solution through the foam.

Example 2

Nylon 12 Microporous Foam Using Salicylic Acid as the FugitiveComposition

Solid Nylon 12 pellets were heated with solid salicylic acid to form a30% (by weight) isotropic solution while using mechanical stirring. Thesolution was heated to about 190° C. in an inert atmosphere and theprocessing vessel was then quenched in liquid nitrogen. The solid foamprecursor obtained was washed with chloroform to remove the salicylicacid.

Characterization of the Nylon 12 foam was accomplished using scanningelectron microscopy (SEM) and revealed a pore size of 50 to 100 microns.Continuous porosity was verified using the dye-transport methoddescribed in Example 1.

Example 3

Nylon 12 Microporous Foam Using Naphthalene

Solid Nylon 12 pellets were heated with solid naphthalene to form a 30%(by weight) isotropic solution while using mechanical stirring. Thesolution was heated to about 190° C. in an inert atmosphere and thevessel was then quenched in liquid nitrogen. The solid foam precursorobtained was washed with methanol which was cooled in liquid nitrogen toremove the naphthalene.

Characterization of the Nylon 12 form was accomplished using SEM andrevealed a pore size of 30 to 50 microns. The dye transport method wasused to verify the foam continuous porosity.

Example 4

Polyethylene Microporous Foam Using Naphthalene

Solid, high-density polyethylene pellets were heated with solidnaphthalene to form a 30% (by weight) isotropic solution while applyingmechanical stirring. The solution was heated to about 150° C. in aninert atmosphere and the vessel was then quenched in liquid nitrogen.The solid foam precursor obtained was washed with chloroform to removethe naphthalene.

Characterization of the polyethylene foam was accomplished using SEM andBET surface area analysis. The polyethylene foam was found to have poresranging from 5 to 50 microns in diameter and a surface area of 2.3square meters/gram. Continuous microporosity was verified using the dyetransport method.

Example 5

Polypropylene Microporous Foam Using Naphthalene

Solid isotactic polypropylene pellets were heated with solid naphthaleneto form a 20% (by weight) isotactic solution while applying mechanicalstirring. The solution was heated to about 170° C. in an inertatmosphere and the processing vessel was then quenched in liquidnitrogen. The solid foam precursor obtained was washed with chloroformto remove the naphthalene.

Characterization of the polyethylene foam was accomplished using SEM andrevealed pores ranging from i to 50 microns in diameter. Continuousporosity was verified using the dye transport method.

Example 6

Polycaprolactone Microporous Foam Using Naphthalene

Solid polycaprolactone (PCL) pellets were heated with solid naphthaleneto form 20%, (by weight) isotropic solutions while applying mechanicalstirring. The solutions were heated close to, but not exceeding, 140° C.in an inert atmosphere and the processing vessel was then quenched inliquid nitrogen. The solid foam precursor obtained was washed withhexane to remove the naphthalene.

Characterization of the polycaprolactone foams were accomplished usingSEM and revealed pore sizes of 5 to 50 microns. Continuous porosity wasverified using the dye transport method. Upon repeating this process,using 10, 20, 30 and 40 weight percent PCL to form foam precursors bycasting into a precooled metallic mold, foams were obtained having pureporosity of 50 to 200μ depending on composition.

Example 7

Nylon 6 Microporous Foam Using Tetramethylene Sulfone

Solid Nylon 6 pellets were heated with tetramethylene sulfone to form a20% (by weight) isotropic solution while applying mechanical stirring.The solution was heated to about 250° C. in an inert atmosphere and theprocess vessel was then quenched in liquid nitrogen. The solid foamprecursor obtained was washed with methanol to remove the tetramethylenesulfone. Continuous porosity was verified using the dye transfer method.

Characterization of the nylon 6 foam was accomplished using SEM andrevealed a pore size of 2 to 5 microns.

Example 8

Absorbable Microporous Foam Using Naphthalene

The absorbable copolyester of this example was prepared by catalyzedpolycondensation of 75/25 (molar ratio) of diemthylterephthalate/diethyl oxalate and 1.2 molar excess of trimethyleneglycol in the presence of about 0.05 percent (by mole) stannous octoateas a catalyst. The polymerization was conducted in two stages. Thefirst, the prepolymerization stage, was conducted at a temperature of150°-180° C. under nitrogen at ambient pressure for about 6 hours. Thesecond stage, post polymerization, was conducted under reduced pressure(less than 1 mmHg) at 180°-210° C. for about 8 hours. The resultingpolymer was cooled, ground, and dried before use. The polymer exhibitedan inherent viscosity (in CHCl₃ at 30° C.) of about 1.0 and a Tm ofabout 127° C.

Solid synthetic absorbable polyester was heated with naphthalene to forma 20% (by weight) isotropic solution while applying mechanical stirring.The solution was heated to about 230° C. in an inert atmosphere and theprocessing vessel was then quenched in liquid nitrogen. The solid foamprecursor obtained was washed with n-hexane to remove the naphthalene.The purified foam exhibited the same inherent viscosity as that of thestarting polymer.

Characterization of this absorbable polyester foam was accomplished bySEM.

Example 9

Absorbable Microporous Copolycaprolactone Foam Using Naphthalene

A solid absorbable copolycaprolactone (90/10 Caprolactone/Glycolidecopolymer) was heated with naphthalene to form a 20% (by weight)isotropic solution while applying mechanical stirring. The solution washeated up to 120° C. in an inert atmosphere and the processing vesselwas then quenched in liquid nitrogen. The solid foam precursor obtainedwas washed with n-hexane to remove the naphthalene. The inherentviscosity (in CHCl₃ @30° C.) of the foam was the same as that of thestarting polymer (about 1.0).)

Characterization of this absorbable foam was accomplished using SEM andindicated a pore size of 1-150 microns. The continuous porosity wasverified using the dye transport method.

Example 10

Absorbable Microporous 95/5 Copolycaprolatone Foam Using Naphthalene

A solid synthetic absorbable polyester (95/5 Caprolactone/Glycolidecopolymer) was heated with naphthalene to form a 20% (by weight)isotropic solution while applying mechanical stirring. The solution washeated up to 110° C. in an inert atmosphere and the processing vesselwas then quenched in liquid nitrogen. The solid foam precursor obtainedwas washed with n-hexane to remove the naphthalene. The purified foamexhibited the same inherent viscosity (in CHCl₃ @30° C.) as the startingpolymer (about 0.8).

Characterization of the absorbable polyester foam was accomplished usingSEM and indicated a pore size of 1-200 μm. The continuous porosity wasverified by the dye diffusion method.

Example 11

Texturing of PEEK (Poly(ether-ether ketone) Film Using Naphthalene

A PEEK 10 mil-thick film sample (STABAR k200 manufactured by I.C.I.) washeated with naphthalene in an inert atmosphere for 2.5 hours at atemperature between 225° and 250° C. The treated film was removed andallowed to air cool at room temperature. The solid naphthalene wasremoved from the "surface" foam precursor using n-hexane after soakingfor about 3 days.

Characterization of the resultant film surface was accomplished usingSEM. A porous surface was evident with pore size diameters as small as 1micron. The depth of the microporous layer was about 2-10 μm.

Example 12

Texturing of PEEK Film Using Salicylic Acid

A 10 mil thick PEEK film (STABAR K200) was heated with salicylic acid inan inert atmosphere for approximately 2 hours at a temperature ofapproximately 240° C. After air cooling the isolated film at roomtemperature, the solid salicylic acid was removed from the "surface"foam precursor using methanol after soaking for about 3 days.

Characterization of the resultant film surface was accomplished usingSEM. A porous surface was evident with pore size diameters at or below 1micron. The depth of the microporous layer was about 5-10 μm.

Example 13

Texturing of a Solid PEEK Coupon

A solid PEEK coupon was placed in liquid anthracene and maintained in aninert atmosphere for 3 hours at a temperature of approximately 260° C.After isolating and air cooling the polymer at room temperature, thesolid anthracene was removed from the foam precursor obtained withhexane.

Characterization of the resultant sample surface was accomplished usingSEM. A porous surface was evident with pore size diameters ranging from1 to 50 micron. The depth of the microporous layer was shown to be about20-200 μm.

Example 14

Extrusion of Microporous Polycaprolactone (PCL) Foam Fibers

Solid PCL was heated with naphthalene to form a 40% (by weight)isotropic solution while applying mechanical stirring. The solution washeated up to 145° C. in an inert atmosphere and the processing vesselwas then quenched in liquid nitrogen. The co-solidified PCL/naphthalenefoam precursor was then melt extruded at about 100° C. using a capillaryequipped with a 40 mil die. The resulting filaments of foam precursorwere air cooled and then washed with n-hexane to remove the naphthaleneand produce PCL foam fibers. The inherent viscosity of the purifiedfilaments was the same as that of the starting polymer (about 2.2 inCHCl₃ @30° C.).

Characterization of the PCL foam fibers was accomplished using SEM toascertain their microporosity. The pore size ranged from 1-5 μm.

Although the invention has been described with reference to itspreferred embodiments, those of ordinary skill in the art may, uponreading this disclosure, appreciate changes and modifications which maybe made and which do not depart from the scope and spirit of theinvention as described above and claimed below.

What is claimed is:
 1. A foam comprising:an organic polymeric matrixwith continuous, open-cell pores dispersed therein; and living cellsproducing at least one product, the living cells contained in the pores,the foams produced by a process comprising the steps of:combining anorganic polymer with a fugitive composition that is a solid cristallinematerial that melts above 25° C. co-melting and co-dissolving thefugitive composition with the polymer to produce a substantiallyisotropic solution; solidifying the isotropic solution to produce a foamprecursor containing crystals of the fugitive composition; removing thecrystals of the fugitive composition from the foam precursor to producea continuous, open-cell foam; and adding selected living cells to thefoam for inhabiting the pores and producing at least one product.
 2. Thefoam of claim 1, wherein the foam is of a predetermined shape suitablefor implantation into a living skeleton for repairing a wound and the atleast one product includes a bone morphogenic protein.
 3. The foam ofclaim 1, wherein the foam is adapted for implantation into a living bodyand the cells produce at least one biologically active compound thatpromotes reconstruction of damaged body tissue.
 4. The foam of claim 1,wherein the cells utilize a nutrient medium to produce the product. 5.The foam of claim 4, wherein the foam is in the form of hollow fibers.6. The foam of claim 2, wherein the organic polymer is a bioabsorbablepolymer.
 7. The foam of claim 3, wherein the organic polymer is abioabsorbable polymer.
 8. The foam of claim 6, wherein the bioabsorbablepolymer is selected from the group consisting of polylactic acid,polyglycolic acid, polyalkylene oxalates, poly-p-dioxane,polyanhydrides, polymorpholinediones, polycaprolactone, and copolymersthereof.
 9. The foam of claim 7, wherein the bioabsorbable polymer isselected from the group consisting of polylactic acid, polyglycolicacid, polyalkylene oxalates, poly-p-dioxane, polyanhydrides,polymorpholinediones, polycaprolactone, and copolymers thereof.
 10. Thefoam of claim 2, wherein the foam is shaped as a prosthetic implant. 11.The foam of claim 3, wherein the foam is shaped as a prosthetic implant.12. The foam of claim 1, wherein the pore diameter is in the range ofabout 1 micron to about 400 microns.
 13. The foam of claim 1, whereinthe living cells are adhered to walls of the pores.